Alpha 1-antitrypsin deficiency overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overview

Alpha 1-antitrypsin deficiency (A1AD or Alpha-1) is a genetically inherited disorder that results in defective production of alpha 1-antitrypsin. Alpha 1-antitrypsin deficiency (A1AD) was discovered in 1963 by Carl-Bertil Laurell and Eriksson at the University of Lund, Sweden. In 1969, Sharp et al was the first to discover the association between liver disease and development of A1AD. There is no established system for the classification of alpha 1-antitrypsin deficiency. Alpha 1-antitrypsin (A1AT) is synthesized and secreted mainly by hepatocytes. Alpha 1-antitrypsin (A1AT) protects the lungs from proteases like the neutrophil elastase enzyme. Genetic mutation in the SERPINA1 gene results in decreased levels of alveolar alpha1 antitrypsin. Proteases accumulate in the alveoli causing a destruction of alveolar walls and resultant emphysema. Accumulation of alpha1-antitrypsin in hepatocytes results in chronic liver disease. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli. In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung. Alpha 1-antitrypsin deficiency has to be differentiated from other conditions with similar presentation like autoimmune hepatitis, bronchiectasis, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, primary ciliary dyskinesia (Kartagener Syndrome), viral hepatitis. Alpha 1-antitrypsin deficiency (A1AD) is more common in people of Northern European, Iberian, and Saudi Arabian descent. First degree relatives of patients with known AAT deficiency are at an increased risk for the condition. Smoking is risk factor for development of serious lung disease in patients with AAT deficiency. Risk for lung disease also increases with exposure to dust, fumes, or other toxic substances. According to the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), all COPD patients should be screened for AATD at least once in their lifetime. All patients with unexplained liver disease with or without respiratory symptoms should be evaluated for alpha1-antitrypsin deficiency AATD. If left untreated, not all patients with deficient gene develop symptomatic emphysema or cirrhosis. The symptoms of alpha1-antitrypsin deficiency (AATD) in the first two decades of life are mainly of associated liver disease progressing to pulmonary manifestations appear later in life. Emphysema is seen in nonsmokers in the fifth decade of life and during the fourth decade of life in smokers. Less common associations are panniculitis and cytoplasmic antineutrophil antibody‒positive vasculitis. The most common cause of death is emphysema. Chronic liver disease is the second most common cause of death. Common complications of AATD include pneumothorax, pneumonia, acute exacerbation of airflow obstruction, and respiratory failure. Physical examination of patients with AATD is usually remarkable for signs characteristic of increased respiratory work, airflow obstruction and hyperinflation that varies according to the severity of emphysema. A reduced concentration of serum alpha1-antitrypsin levels is diagnostic of AATD. Laboratory findings consistent with the diagnosis of AATD include moderate-to-severe airflow obstruction with an FEV1 in the range of 30-40% of the predicted value, reduced vital capacity, increased lung volumes secondary to air trapping (residual volume >120% of predicted value) are usually present, and diffusing capacity values are reduced substantially (<50% of predicted value) in most symptomatic patients. On chest X-ray alpha1-antitrypsin deficiency (AATD) emphysema presents as a hyperlucent appearance because healthy tissue has been destroyed. On High-resolution CT (HRCT) scan of the chest, hypoattenuated areas resulting from a lack of lung tissue are panlobular and characteristic lower zone predominance. Patients with low or borderline serum levels are tested with phenotyping (serum levels < 100 mg/dL) by isoelectric focusing (IEF) is the most commonly used method to definitively detect the alpha1-antitrypsin phenotype that indicates a risk for AATD. Genotyping uses DNA extracted from circulating mononuclear blood cells that utilizes DNA amplification techniques with melt-curve analysis. Recommendations based on treatment guidelines for AATD include: Alpha 1-antitrypsin enzyme repletion, smoking cessation, long-acting inhaled bronchodilators, preventive vaccinations against influenza and pneumococcus, pulmonary rehabilitation for patients with functional impairment, supplemental oxygen if needed, lung transplantation, treatment of COPD exacerbation in all patients of AATD should include AAT repletion. Lung transplantation may be recommended for some patients with end-stage lung disease. Effective measures for the primary prevention of alpha 1-antitrypsin deficiency includes vaccination against hepatitis A and hepatitis B to decrease the risk of liver complications. Secondary prevention strategies following alpha1-antitrypsin deficiency (AATD) includes avoid cigarette smoking. Smoking accelerates the progression of emphysema in severely deficient individuals by as much as 15 years when compared to their nonsmoking controls. The ATS/ERS AAT Deficiency Task Force recommends that all exacerbations with purulent sputum be treated with early antibiotic therapy. Prompt and effective treatment of infections provides protection from additional lung injury from an influx of neutrophils into the alveolus.

Historical Perspective

Alpha 1-antitrypsin deficiency (A1AD) was discovered in 1963 by Carl-Bertil Laurell (1919–2001) and Eriksson at the University of Lund, Sweden. In 1969, Sharp et al were the first to discover the association between liver disease and development of A1AD.

Classification

There is no established system for the classification of alpha 1-antitrypsin deficiency.

Pathophysiology

Alpha 1-antitrypsin (A1AT) is synthesized and secreted mainly by hepatocytes. However, other sources of the enzyme include macrophages and bronchial epithelial cells.Alpha1-antitrypsin enzyme is a member of the serine protease inhibitor (serpin) family of proteins. Alpha 1-antitrypsin (A1AT) protects the lungs from proteases like the neutrophil elastase enzyme.Genetic mutation in the SERPINA1 gene results in decreased levels of alveolar alpha1 antitrypsin. Proteases accumulate in the alveoli causing a destruction of alveolar walls and resultant emphysema. Excess alpha1-antitrypsin in hepatocytes results in chronic liver disease. SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule. This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency. On cut section of the lung, emphysematous process is evidenced by dilated air spaces and loss of lung parenchyma. Superimposed infections can result in scarring. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli. In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung.

Differentiating Alpha 1-antitrypsin deficiency from Other Diseases

Alpha 1-antitrypsin deficiency has to be differentiated from other conditions with similar presentation like autoimmune hepatitis, bronchiectasis, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, primary ciliary dyskinesia (Kartagener syndrome), and viral hepatitis.

Epidemiology and Demographics

Alpha 1-antitrypsin deficiency (A1AD) is more common in people of Northern European, Iberian, and Saudi Arabian descent. Most researchers believe it is markedly underrecognized. The incidence of AATD is estimated to be 20 cases per 100,000 individuals worldwide. The prevalence of AATD is estimated to be 70,000-100,000 cases annually. Alpha1-antitrypsin deficiency (AATD) is one of most common lethal genetic diseases among the adult white population. AATD has estimated 117 million carriers and 3.4 million affected individuals.

Risk Factors

First degree relatives of patients with known AAT deficiency are at an increased risk for the condition. Smoking is a risk factor for the development of serious lung disease in patients with AAT deficiency. The risk for lung disease also increases with exposure to dust, fumes, or other toxic substances.

Screening

According to the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), all COPD patients should be screened for AATD at least once in their lifetime. All patients with an unexplained liver disease with or without accompanying respiratory symptoms should be evaluated for AATD.

Natural History, Complications, and Prognosis

If left untreated, not all patients with deficient gene develop symptomatic emphysema or cirrhosis. In symptomatic patients, the median time between observation of symptoms and diagnosis is approximately 8 years. The symptoms of alpha1-antitrypsin deficiency (AATD) in the first two decades of life are mainly of the associated liver disease progressing to pulmonary manifestations appear later in life. Emphysema, is seen in nonsmokers in the fifth decade of life and during the fourth decade of life in smokers. Less common associations are panniculitis and cytoplasmic antineutrophil cytoplasmic antibody-positive vasculitis. The most common cause of death is emphysema. Chronic liver disease is the second most common cause of death. Common complications of AATD include pneumothorax, pneumonia, acute exacerbation of airflow obstruction, and respiratory failure. Prognosis depends on how patients are identified. Patients identified as a result of screening often have an excellent prognosis. Those identified because of their symptoms have a poor prognosis.

Diagnosis

Diagnostic Criteria

A reduced concentration of serum alpha 1-antitrypsin levels is diagnostic of alpha 1-antitrypsin deficiency (AATD).

History and Symptoms

Alpha 1-antitrypsin deficiency (A1AD) may be slow to manifest in symptom onset in newborns. As patient ages, liver dysfunction will occur. The hallmark of AATD is dyspnea. A positive history of dyspnea and liver cirrhosis or chronic hepatitis is suggestive of AATD. The presentation of the disease varies depending on the type of mutation associated with AATD. Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, wheezing, rhonchi and rales (may appear to be due to recurring respiratory infections), and obstructive asthma that does not respond to treatment.

Physical Examination

Physical examination of patients with AATD is usually remarkable for signs characteristic of increased respiratory work, airflow obstruction and hyperinflation that varies according to the severity of emphysema. Patients with mild emphysema usually have no abnormal findings on physical examination. Patient may appear normal. Those with severe emphysema develop tachypnea and pursed-lip breathing. Other findings on physical examination include pulsus paradoxus, scalene muscle retraction, intercostal muscle retraction, wheezing, hepatomegaly, hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity, and distant heart sounds.

Laboratory Findings

A reduced concentration of serum alpha1-antitrypsin levels is diagnostic of AATD. Laboratory findings consistent with the diagnosis of AATD include moderate-to-severe airflow obstruction with an FEV1 in the range of 30-40% of the predicted value, reduced vital capacity, increased lung volumes secondary to air trapping (residual volume >120% of predicted value) are usually present, diffusing capacity values are reduced substantially (<50% of predicted value) in most symptomatic patients. Serum alpha1-antitrypsin levels are determined by nephelometry. Serum testing is used for diagnostic testing in those patients with family histories compatible with alpha1-antitrypsin deficiency or with siblings with known alpha1-antitrypsin deficiency. In patients with clinical features that are highly suggestive of alpha1-antitrypsin deficiency but whose serum levels are within the reference range the next best step is to perform a functional assay of alpha1 antiprotease, which measures the ability of the patient's serum to inhibit human leukocyte elastase. Perform liver function tests in patients with low or borderline levels of alpha1-antitrypsin. Measurement of serum transaminases, bilirubin, albumin, and routine clotting function (activated partial thromboplastin time and international normalized ratio).

Imaging Findings

X-ray

On chest Xray of Alpha1-antitrypsin deficiency (AATD), emphysema presents as a hyperlucent appearance because the healthy tissue has been destroyed. Affected regions can also present as oligemic areas on x-ray because they lack the normal rich pattern of branching blood vessels. A characteristic feature observed in about two thirds of PiZZ patients of alpha1-antitrypsin deficiency is that the emphysema has a striking basilar distribution. In contrast, cigarette smoking is associated with a more severe apical disease.

CT scan

On High-resolution CT (HRCT) scan of the chest, hypoattenuated areas result from a lack of lung tissue. As tissue is lost, pulmonary vessels appear smaller, fewer in number, and spread farther apart. Mild forms of alpha1-antitrypsin disease can be missed on HRCT scanning. However, when the disease is moderate, panlobular and characteristic lower zone predominance is observed. Severe forms may be indistinguishable from severe centrilobular emphysema. normal lung structures have been replaced by abnormal airspaces CT of the abdomen shows evidence of hepatomegaly or cirrhosis or hepatocellular carcinoma.

Other Diagnostic Studies

Patients with low or borderline serum levels are tested with phenotyping (serum levels < 100 mg/dL) by isoelectric focusing (IEF) is the most commonly used method to definitively detect the alpha1-antitrypsin phenotype that indicates a risk for AATD. Genotyping uses DNA extracted from circulating mononuclear blood cells that utilize DNA amplification techniques with melt-curve analysis.

Treatment

Medical Therapy

Treatment guidelines for AATD include: alpha 1 antitrypsin enzyme repletion, smoking cessation, long-acting inhaled bronchodilators, preventive vaccinations against influenza and pneumococcus, pulmonary rehabilitation for patients with functional impairment, supplemental oxygen if needed, lung transplantation, treatment of COPD exacerbation in all patients of AATD should include AAT repletion.

Surgery

Lung transplantation may be recommended for some patients with end-stage lung disease. Alpha 1-antitrypsin deficiency accounts for about 5% of all lung transplantation performed in the United States. Five year survival rates following lung transplant is approximately 50%. The rate of FEV1 decline among AATD patients who received double lung transplantation was faster than among single lung recipients. The estimated median survival time was 11 years in transplant recipients versus 5 years in controls. Lung volume reduction surgery (LVRS) can help relieve dyspnea and improve exercise capacity in patients with emphysema. Data regarding the efficacy of LVRS for individuals with AATD is limited and generally less favorable in magnitude and duration of FEV1 improvement.

Primary Prevention

Effective measures for the primary prevention of alpha 1-antitrypsin deficiency includes vaccination against hepatitis A and B is recommended to decrease the risk of liver disease.

Secondary Prevention

Secondary prevention strategies following alpha1-antitrypsin deficiency (AATD) includes avoiding cigarette smoke. Smoking accelerates the progression of emphysema in severely alpha 1 antitrypsin deficient individuals by as much as 15 years when compared to their nonsmoking controls. Pneumonia and annual influenza vaccines will help prevent respiratory infections in patients with alpha1-antitrypsin deficiency (AATD). The ATS/ERS AAT Deficiency Task Force recommends that all exacerbations with purulent sputum be treated with early antibiotic therapy. Prompt and effective treatment of infections may provide protection from additional lung injury from an influx of neutrophils into the alveolus.

Future or Investigational therapies

Treatment options for alpha 1-antitrypsin deficiency currently being studied include recombination and inhaled forms of alpha 1-antitrypsin. Other experimental therapies are aimed at the prevention of polymer formation in the liver. Gene therapy to deliver recombinant adeno-associated virus carrying the human AAT (alpha 1 antitrypsin) gene is also being investigated as an alternate treatment approach.

References



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